Browsing by Subject "immunotherapy"

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  • Sousa-Pinto, Bernardo; Azevedo, Luis Filipe; Sa-Sousa, Ana; Vieira, Rafael Jose; Amaral, Rita; Klimek, Ludger; Czarlewski, Wienczyslawa; Anto, Josep M.; Bedbrook, Anna; Kvedariene, Violeta; Ventura, Maria Teresa; Ansotegui, Ignacio J.; Bergmann, Karl-Christian; Brussino, Luisa; Canonica, G. Walter; Cardona, Victoria; Carreiro-Martins, Pedro; Casale, Thomas; Cecchi, Lorenzo; Chivato, Tomas; Chu, Derek K.; Cingi, Cemal; Costa, Elisio M.; Cruz, Alvaro A.; De Feo, Giulia; Devillier, Philippe; Fokkens, Wytske J.; Gaga, Mina; Gemicioglu, Bilun; Haahtela, Tari; Ivancevich, Juan Carlos; Ispayeva, Zhanat; Jutel, Marek; Kuna, Piotr; Kaidashev, Igor; Kraxner, Helga; Larenas-Linnemann, Desiree E.; Laune, Daniel; Lipworth, Brian; Louis, Renaud; Makris, Michael; Monti, Riccardo; Morais-Almeida, Mario; Moesges, Ralph; Mullol, Joaquim; Odemyr, Mikaela; Okamoto, Yoshitaka; Papadopoulos, Nikolaos G.; Patella, Vincenzo; Nhan Pham-Thi; Regateiro, Frederico S.; Reitsma, Sietze; Rouadi, Philip W.; Samolinski, Boleslaw; Sova, Milan; Todo-Bom, Ana; Taborda-Barata, Luis; Tomazic, Peter Valentin; Toppila-Salmi, Sanna; Sastre, Joaquin; Tsiligianni, Ioanna; Valiulis, Arunas; Wallace, Dana; Waserman, Susan; Yorgancioglu, Arzu; Zidarn, Mihaela; Zuberbier, Torsten; Fonseca, Joao Almeida; Bousquet, Jean; Pfaar, Oliver (2022)
    Background Evidence regarding the effectiveness of allergen immunotherapy (AIT) on allergic rhinitis has been provided mostly by randomised controlled trials, with little data from real-life studies. Objective To compare the reported control of allergic rhinitis symptoms in three groups of users of the MASK-air(R) app: those receiving sublingual AIT (SLIT), those receiving subcutaneous AIT (SCIT), and those receiving no AIT. Methods We assessed the MASK-air(R) data of European users with self-reported grass pollen allergy, comparing the data reported by patients receiving SLIT, SCIT and no AIT. Outcome variables included the daily impact of allergy symptoms globally and on work (measured by visual analogue scales-VASs), and a combined symptom-medication score (CSMS). We applied Bayesian mixed-effects models, with clustering by patient, country and pollen season. Results We analysed a total of 42,756 days from 1,093 grass allergy patients, including 18,479 days of users under AIT. Compared to no AIT, SCIT was associated with similar VAS levels and CSMS. Compared to no AIT, SLIT-tablet was associated with lower values of VAS global allergy symptoms (average difference = 7.5 units out of 100; 95% credible interval [95%CrI] = -12.1;-2.8), lower VAS Work (average difference = 5.0; 95%CrI = -8.5;-1.5), and a lower CSMS (average difference = 3.7; 95%CrI = -9.3;2.2). When compared to SCIT, SLIT-tablet was associated with lower VAS global allergy symptoms (average difference = 10.2; 95%CrI = -17.2;-2.8), lower VAS Work (average difference = 7.8; 95%CrI = -15.1;0.2), and a lower CSMS (average difference = 9.3; 95%CrI = -18.5;0.2). Conclusion In patients with grass pollen allergy, SLIT-tablet, when compared to no AIT and to SCIT, is associated with lower reported symptom severity. Future longitudinal studies following internationally-harmonised standards for performing and reporting real-world data in AIT are needed to better understand its 'real-world' effectiveness.
  • Bousquet, Jean; Pfaar, Oliver; Agache, Ioana; Bedbrook, Anna; Akdis, Cezmi A.; Canonica, G. Walter; Chivato, Tomas; Al-Ahmad, Mona; Abdul Latiff, Amir H.; Ansotegui, Ignacio J.; Bachert, Claus; Baharuddin, Abdullah; Bergmann, Karl-Christian; Bindslev-Jensen, Carsten; Bjermer, Leif; Bonini, Matteo; Bosnic-Anticevich, Sinthia; Bosse, Isabelle; Brough, Helen A.; Brussino, Luisa; Calderon, Moises A.; Caraballo, Luis; Cardona, Victoria; Carreiro-Martins, Pedro; Casale, Tomas; Cecchi, Lorenzo; Cepeda Sarabia, Alfonso M.; Chkhartishvili, Ekaterine; Chu, Derek K.; Cirule, Ieva; Cruz, Alvaro A.; Czarlewski, Wienczyslawa; del Giacco, Stefano; Demoly, Pascal; Devillier, Philippe; Dokic, Dejan; Durham, Stephen L.; Ebisawa, Motohiro; El-Gamalt, Yehia; Emuzyte, Regina; Gamkrelidze, Amiran; Fauquert, Jean Luc; Fiocchi, Alessandro; Fokkens, Wytske J.; Fonseca, Joao A.; Fontaine, Jean-Francois; Gawlik, Radoslaw; Gelincik, Asli; Gemicioglu, Bilun; Gereda, Jose E.; Gerth van Wijk, Roy; Gomez, R. Maximiliano; Gotua, Maia; Grisle, Ineta; Guzman, Maria-Antonieta; Haahtela, Tari; Halken, Susanne; Heffler, Enrico; Hoffmann-Sommergruber, Karin; Hossny, Elham; Hrubisko, Martin; Irani, Carla; Ivancevich, Juan Carlos; Ispayeva, Zhanat; Julge, Kaja; Kaidashev, Igor; Kalayci, Omer; Khaitov, Musa; Klimek, Ludger; Knol, Edward; Kowalski, Marek L.; Kraxner, Helga; Kull, Inger; Kuna, Piotr; Kvedariene, Violeta; Kritikos, Vicky; Lauerma, Antti; Lau, Susanne; Laune, Daniel; Levin, Michael; Larenas-Linnemann, Desiree E.; Lodrup Carlsen, Karin C.; Lombardi, Carlo; Lourenco, Olga M.; Mahboub, Bassam; Malling, Hans-Jorgen; Manning, Patrick; Marshall, Gailen D.; Melen, Erik; Meltzer, Eli O.; Miculinic, Neven; Milenkovic, Branislava; Moin, Mostafa; Montefort, Stephen; Morais-Almeida, Mario; Mortz, Charlotte G.; Mosges, Ralph; Mullol, Joaquim; Namazova Baranova, Leyla; Neffen, Hugo; Nekam, Kristof; Niedoszytko, Marek; Odemyr, Mikaela; O'Hehir, Robyn E.; Ollert, Markus; O'Mahony, Liam; Ohta, Ken; Okamoto, Yoshitaka; Okubo, Kimi; Pajno, Giovanni B.; Palomares, Oscar; Palkonen, Susanna; Panzner, Petr; Papadopoulos, Nikolaos; Park, Hae-Sim; Passalacqua, Giovanni; Patella, Vincenzo; Pawankar, Ruby; Pham-Thi, Nhan; Plavec, Davor; Popov, Todor A.; Recto, Marysia; Regateiro, Frederico S.; Riggioni, Carmen; Roberts, Graham; Rodriguez-Gonzales, Monica; Rosario, Nelson; Rottem, Menachem; Rouadi, Philip W.; Ryan, Dermot; Samolinski, Boleslaw; Sanchez-Borgest, Mario; Serpa, Faradiba S.; Sastre, Joaquin; Scadding, Glenis K.; Shamji, Mohamed H.; Schmid-Grendelmeier, Peter; Schunemann, Holger J.; Sheikh, Aziz; Scichilone, Nicola; Sisul, Juan Carlos; Sofiev, Mikhail; Sole, Dirceu; Sooronbaev, Talant; Soto-Martinez, Manuel; Soto-Quiros, Manuel; Sova, Milan; Schwarze, Jurgen; Skypala, Isabel; Suppli-Ulrik, Charlotte; Taborda-Barata, Luis; Todo-Bom, Ana; Torres, Maria J.; Valentin-Rostan, Marylin; Tomazic, Peter-Valentin; Valero, Antonio; Toppila-Salmi, Sanna; Tsiligianni, Ioanna; Untersmayr, Eva; Urrutia-Pereira, Marilyn; Valiulis, Arunas; Valovirta, Erkka; Vandenplas, Olivier; Ventura, Maria Teresa; Vichyanond, Pakit; Wagenmann, Martin; Wallace, Dana; Walusiak-Skorupa, Jolanta; Wang, De Yun; Waserman, Susan; Wong, Gary W. K.; Yorgancioglu, Arzu; Yusuf, Osman M.; Zernotti, Mario; Zhang, Luo; Zidarn, Mihaela; Zuberbier, Torsten; Jutel, Marek (2021)
  • Fusciello, Manlio; Fontana, Flavia; Tähtinen, Siri; Capasso, Cristian; Feola, Sara; da Silva Lopes Martins, Beatriz; Chiaro, Jacopo; Peltonen, Karita; Ylösmäki, Leena; Ylösmäki, Erkko; Hamdan Hissaoui, Firas; Kari, Otto K.; Ndika, Joseph; Alenius, Harri; Urtti, Arto; Hirvonen, Jouni T.; Santos, Hélder A.; Cerullo, Vincenzo (2019)
    Virus-based cancer vaccines are nowadays considered an interesting approach in the field of cancer immunotherapy, despite the observation that the majority of the immune responses they elicit are against the virus and not against the tumor. In contrast, targeting tumor associated antigens is effective, however the identification of these antigens remains challenging. Here, we describe ExtraCRAd, a multi-vaccination strategy focused on an oncolytic virus artificially wrapped with tumor cancer membranes carrying tumor antigens. We demonstrate that ExtraCRAd displays increased infectivity and oncolytic effect in vitro and in vivo. We show that this nanoparticle platform controls the growth of aggressive melanoma and lung tumors in vivo both in preventive and therapeutic setting, creating a highly specific anti-cancer immune response. In conclusion, ExtraCRAd might serve as the next generation of personalized cancer vaccines with enhanced features over standard vaccination regimens, representing an alternative way to target cancer.
  • Fontana, Flavia; Fusciello, Manlio; Groeneveldt, Christianne; Capasso, Cristian; Chiaro, Jacopo; Feola, Sara; Liu, Zehua; Mäkilä, Ermei; Salonen, Jarno; Hirvonen, Jouni; Cerullo, Vincenzo; Santos, Hélder A. (2019)
    Recent approaches in the treatment of cancer focus on involving the immune system to control the tumor growth. The administration of immunotherapies, like checkpoint inhibitors, has shown impressive results in the long term survival of patients. Cancer vaccines are being investigated as further tools to prime tumor-specific immunity. Biomaterials show potential as adjuvants in the formulation of vaccines, and biomimetic elements derived from the membrane of tumor cells may widen the range of antigens contained in the vaccine. Here, we show how mice presenting an aggressive melanoma tumor model treated twice with the complete nanovaccine formulation showed control on the tumor progression, while in a less aggressive model, the animals showed remission and control on the tumor progression, with a modification in the immunological profile of the tumor microenvironment. We also prove that co-administration of the nanovaccine together with a checkpoint inhibitor increases the efficacy of the treatment (87.5% of the animals responding, with 2 remissions) compared to the checkpoint inhibitor alone in the B16.OVA model. Our platform thereby shows potential applications as a cancer nanovaccine in combination with the standard clinical care treatment for melanoma cancers.
  • Almangush, Alhadi; Leivo, Ilmo; Makitie, Antti A. (2021)
    Oral squamous cell carcinoma (OSCC) forms a major health problem in many countries. For several decades the management of OSCC consisted of surgery with or without radiotherapy or chemoradiotherapy. Aiming to increase survival rate, recent research has underlined the significance of harnessing the immune response in treatment of many cancers. The promising finding of checkpoint inhibitors as a weapon for targeting metastatic melanoma was a key event in the development of immunotherapy. Furthermore, clinical trials have recently proven inhibitor of PD-1 for treatment of recurrent/metastatic head and neck cancer. However, some challenges (including patient selection) are presented in the era of immunotherapy. In this mini-review we discuss the emergence of immunotherapy for OSCC and the recently introduced biomarkers of this therapeutic strategy. Immune biomarkers and their prognostic perspectives for selecting patients who may benefit from immunotherapy are addressed. In addition, possible use of such biomarkers to assess the response to this new treatment modality of OSCC will also be discussed.
  • Harjunpää, Heidi; Llort Asens, Marc; Guenther, Carla; Fagerholm, Susanna C. (2019)
    The immune system and cancer have a complex relationship with the immune system playing a dual role in tumor development. The effector cells of the immune system can recognize and kill malignant cells while immune system-mediated inflammation can also promote tumor growth and regulatory cells suppress the anti-tumor responses. In the center of all anti-tumor responses is the ability of the immune cells to migrate to the tumor site and to interact with each other and with the malignant cells. Cell adhesion molecules including receptors of the immunoglobulin superfamily and integrins are of crucial importance in mediating these processes. Particularly integrins play a vital role in regulating all aspects of immune cell function including immune cell trafficking into tissues, effector cell activation and proliferation and the formation of the immunological synapse between immune cells or between immune cell and the target cell both during homeostasis and during inflammation and cancer. In this review we discuss the molecular mechanisms regulating integrin function and the role of integrins and other cell adhesion molecules in immune responses and in the tumor microenvironment. We also describe how malignant cells can utilize cell adhesion molecules to promote tumor growth and metastases and how these molecules could be targeted in cancer immunotherapy.
  • Mäki, Toni (Helsingin yliopisto, 2020)
    The human immune system can provide a powerful tool in developing therapies against various cancers. Even though the idea of an immune system actively searching for and disposing of potential mutated tumor cells is over a century old, only recent developments in various fields such as mass spectrometry, immuno-checkpoint blockade strategies and in silico modelling have enabled the realization of the full potential of recruiting immune system to fight cancer and the possibilities of personalized therapies. These therapeutic methods, including but not limited to oncolytic virus therapies, T-cell therapies and cancer vaccines, are based on the body’s ability to recognize mutated antigen peptides presented on the cell surface by MCH-receptors (also known as HLA-receptors in humans) and the disposal of the malignant cells by cytotoxic T-cells. Thus, the capability to map the individual HLA-presented peptidome and differentiate the immunogenic peptides is a foundation for this plethora of therapies and is in focus of ongoing research. This master thesis is a part of a project aiming to set up immunoaffinity-purification/MS based method in order to analyse the ligandome and determine T-cell recognized cancer associated antigens from tumor cells. Objectives of the work: 1. Characterizing tumor cell lines. 2. Immunological assay set up. 3. Collecting cell culture material for the ligandome affinity purification. 4. In silico prediction if the immunogenicity of selected peptides and assessing their source proteins. Methods used: 1. Cell culture. 2. FACS-analysis. 3. MTS-viability assay. 4. Immunological assays (ELISA, ELISPOT). 5. Immunological bioinformatics analysis tools (IEDB) and database search (UniPROT). Results: 1. Flow cytometric analysis provided essential information of the cell line HLA-1 expression. Additional information of PD-L1 expression can be used to evaluate cell line’s immune-evasion abilities. Preliminary MTS assay is used to determine linear range and optimal time frame for the PBMC/cancer cell co-culture killing assay. 2. Interferon γ cytokine secretion was determined by ELISPOT to assess PBMC response against known antigens in a preliminary experiment to approximate usable range for the following antigen specific PBMC assays. ELISA is used to confirm the presence of HLA-I receptors in the ligandome affinity purification eluates and to estimate the efficacy of purification. 3. Feasibility of in silico methods in the prediction of immunogenic peptides was explored. The experiments provided information that can be applied to the further development of the immune ligandome discovery project. In silico methods were successfully used to characterize previously identified HLA-restricted peptides and one previously identified immunogenic T-cell epitope. Even if the data acquired in silico can be considered only nominally verified at this stage, the results are encouraging.
  • Havunen, Riikka; Kalliokoski, Riikka; Siurala, Mikko; Sorsa, Suvi; Santos, Joao M.; Cervera-Carrascon, Victor; Anttila, Marjukka; Hemminki, Akseli (2021)
    Oncolytic viruses provide a biologically multi-faceted treatment option for patients who cannot be cured with currently available treatment options. We constructed an oncolytic adenovirus, TILT-123, to support T-cell therapies and immune checkpoint inhibitors in solid tumors. Adenoviruses are immunogenic by nature, are easy to produce in large quantities, and can carry relatively large transgenes. They are the most commonly used gene therapy vectors and are well tolerated in patients. TILT-123 expresses two potent cytokines, tumor necrosis factor alpha and interleukin-2, to stimulate especially the T-cell compartment in the tumor microenvironment. Before entering clinical studies, the safety and biodistribution of TILT-123 was studied in Syrian hamsters and in mice. The results show that TILT-123 is safe in animals as monotherapy and in combination with an immune checkpoint inhibitor anti-PD-1. The virus treatment induces acute changes in circulating immune cell compartments, but the levels return to normal by the middle of the treatment period. The virus is rapidly cleared from healthy tissues, and it does not cause damage to vital organs. The results support the initiation of a phase 1 dose-escalation trial, where melanoma patients receiving a tumor-infiltrating lymphocyte therapy are treated with TILT-123 (NCT04217473).
  • Juntunen, Maiju (Helsingin yliopisto, 2020)
    Cancer immunotherapy refers to therapy strategies that utilise the mechanisms of the immune system to treat cancer patients. The benefits of the approach include the possibility for specific targeting and utilisation of the host immune system. The treatment methods include cancer vaccines, oncolytic viruses (OVs), cell-based immunotherapies and antibodies. The interplay between the cancer and the immune system has been observed crucial for the progress of the cancer and the success of immunotherapies. An immune inflamed tumour microenvironment has been observed beneficial for the success of several therapy methods. Many immunotherapy methods rely on detecting tumour specific antigens that are used to guide the therapy agent to the target site. This strategy poses challenges when considering tumour immune evasion mechanisms, which can cause downregulation of target antigens, and heterogeneity of tumour cells and patients. OVs have the advantage of not requiring predetermined target structures to exert their effect to the tumour cells. They cause direct tumour cell lysis and induce immune responses, and may be modified to express additional genes, including immunostimulatory agents. However, virus-related immunosuppressive mechanisms and a rapid viral clearance may limit their effects. A Western Reserve (WR) Vaccinia virus (VACV) is a highly oncolytic virus strain but the virus has been observed to suppress the function of the cyclic guanosine monophosphate adenosine monophosphate synthase – stimulator of interferon genes (cGAS STING) innate immune pathway which has been shown to have a significant role in anti-tumour immune responses. The aim of this study was to create a WR VACV encoding a dominantly active (D A) STING and to determine whether the virus is capable of activating the cGAS STING pathway. The effects were compared to a corresponding virus vvdd tdTomato that does not have the STING encoding gene. The pathogenicity of viruses was controlled by a double deletion of the thymidine kinase and vaccinia growth factor genes which restricts the virus replication to tumour cells. Transgene fragments were cloned from template plasmids by polymerase chain reactions (PCRs) and joined together in a Gibson Assembly (GA) reaction to form a STING-P2A-eGFP gene insert. The insert was attached to a shuttle vector pSC65-tdTomato by restriction enzyme digestion, ligation and transformation in Escherichia coli. The correct transgene plasmid construct was verified by Sanger sequencing and PCRs. The transgene was inserted to a modified WR VACV vvdd-tdTomato-hDAI by a homologous recombination. The newly created VVdd STING-P2A-eGFP virus was purified by plaque purification. The STING protein expression was studied by an immunocytochemistry (ICC) assay. The immune signalling pathway activation was examined by testing nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation in RAW-Blue cells and dendritic cell activation and maturation in JAWS II cells. The cell viability after iinfection was studied with four cell lines; A549, B16-F10, HEK293 and MB49. The D-A STING expressing virus was produced successfully. The ICC experiment verified the capability of the VVdd STING-P2A eGFP to produce the STING protein in the infected cells. The preliminary findings indicate that the VVdd STING-P2A-eGFP virus activates the NF-κB signalling in the RAW-Blue cells and that the activation is dependent on the STING expression. The activation level is relative to the infection concentration at MOI range 0,001 to 0,1. The findings suggest that the VVdd-STING-eGFP virus can induce innate immune signalling via the STING pathway. The reference virus did not activate the signalling. The in vitro experiments also indicated that the STING virus may induce DC activation and maturation. We observed a trend of CD86 and CD40 expression upregulation on the JAWS II DCs. The effects to the cell viability were inconclusive. More studies should be conducted to verify the results. The effects of the virus should be studied in more advanced cancer models that take into account the complexity of the immune system. These preliminary results indicate the that the VVdd-STING-P2A-eGFP virus could stimulate the immune signalling through the STING pathway.
  • Jansen, Y. J. L.; Rozeman, E. A.; Mason, R.; Goldinger, S. M.; Foppen, M. H. Geukes; Hoejberg, L.; Schmidt, H.; van Thienen, J.; Haanen, J. B. A. G.; Tiainen, L.; Svane, I. M.; Mäkelä, S.; Seremet, T.; Arance, A.; Dummer, R.; Bastholt, L.; Nyakas, M.; Straume, O.; Menzies, A. M.; Long, G.; Atkinson, Jeffrey; Blank, C. U.; Neyns, B. (2019)
    Background Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established. Patients and Methods This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N=167) or nivolumab (N=18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia. Results Median time on treatment was 12months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response. Conclusions In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for >6months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients. Clinical trial registration NCT02673970 (https://clinicaltrials.gov/ct2/show/NCT02673970?cond=melanoma&cntry=BE&city=Jette&rank=3)
  • Mahlamäki, Kasper (Helsingin yliopisto, 2019)
    Syöpätautien yleisyys lisääntyy kaikkialla maailmassa väestön vanhetessa ja Suomessakin todetaan vuosittain noin 35 000 uutta syöpää, joihin kuolee noin 13 000 henkeä. Syövän lääkehoidon painopiste on siirtymässä laajalti elimistön soluja tuhoavista sädehoidosta ja solunsalpaajista kohti potilaan omaa immuunipuolustusta syöpää vastaan ohjaavia immuno-onkologisia lääkkeitä. Immuno-onkologisilla lääkkeillä, kuten tarkastuspiste-estäjiin kuuluvilla PD-1-vasta-aineilla on saavutettu jopa pysyviä remissioita useassa vaikeahoitoisessa syövässä. Valitettavasti vain pieni osa immunologisilla syöpälääkkeillä hoidetuista potilaista saa niiden täyden hyödyn ja hoitovasteen laajentaminen koko potilasjoukkoon on osoittautunut ongelmalliseksi. Tutkielmani kirjallisuuskatsauksessa käsitellään rintasyöpää yleisesti, sekä syvennytään rintasyövän prekliinisiin tutkimusmalleihin ja rintasyöpäpotilaan immuno-onkologiavasteen ennustetekijöihin. Kokeellisen laboratoriotutkimusosuuden tavoitteina oli korreloida rintasyöpänäytteiden leukosyytti-infiltraation taso kasvaimen Myc- ja PD-L1-ekspressioon, mitata solulinjojen ja tutkimusryhmämme kehittämien PDEC-eksplanttien immuuniaktivaatiota, sekä arvioida näiden tutkimusten tulosten avulla rintasyöpäpotilaan kasvainnäytteestä kasvattamiemme PDEC-kudosviljelmien potentiaalia rintasyövän immuno-onkologisessa tutkimuksessa. Löysin tutkimalla primäärikasvainten ja PDEC-eksplanttien ominaisuuksia immunohistokemialla sekä qRT-PCR:llä korrelaation primäärikasvaimen leukosyyttimäärän sekä PDEC-viljelmien qRT-PCR:llä mitatun immuuniaktiivisuuden välille: kasvaimen korkea leukosyyttipitoisuus vaikuttaa olevan yhteydessä PDEC-viljelmien suurempaan immuuniaktiivisuuteen. Mielenkiintoista oli havaita, että vaikka immuunisolujen aktivoimiseen käytetyn Immunocultin tulisi aktivoida kaikkia T-soluja, niin edes runsas kasvaimen strooman leukosyytti-infiltraatio ei aiheuttanut qRT-PCR:llä tehdyissä immuuniaktivaatiomittauksissa menetelmän käyttöä häiritseviä vääriä positiivisia tuloksia. Tulosteni perusteella PDEC-eksplantit kykenevät kuvaamaan rintasyöpäpotilaiden kasvainkohtaisia immuuniaktivaatioeroja, mikä korostaa niiden soveltuvuutta immuno-onkologiseen tutkimukseen.
  • Bouhlal, Jonas Otto Vilhelm (Helsingin yliopisto, 2022)
    Despite of great advancements in the field of cancer therapy in the past decades, the 5-year survival of acute myeloid leukaemia (AML) patients remains low with high mortality especially in elderly patients, in whom the disease is most often observed. Poor prognosis often results from complex heterogenous molecular abnormalities defining the progress of the disease, while making it more difficult to treat due to intensive treatments only being feasible for younger patients. Our increased understanding of cancer immunology and the potential of immunotherapy has, however, led to promising therapeutic innovations, which give hope for discovering long-lasting and effective treatment options. Natural killer (NK) cell-based immunotherapies are amongst the emerging novel therapeutic approaches that aim to target malignant cells with less toxicity and improved applicability. Using high-throughput drug sensitivity and resistance testing combined with single cell RNA (scRNA) sequencing, this study focused on finding drug compounds that could synergise with NK cells to improve their effectiveness in killing leukemic cells. In this study, many drugs showed promising results in being able to potentiate NK cell cytotoxicity, with daporinad and pevonedistat showing the most notable differences when compared to controls. The potentiating effect of Janus kinase (JAK) inhibitors also suggested a method of increasing NK cell activity against leukemic cells through downregulation of major histocompatibility complex (MHC) class I molecules. In conclusion, findings shed light on the synergetic potential of drugs and NK cells, giving hope for clinically relevant findings following further validation and testing.
  • Hemminki, Otto; Parviainen, Suvi; Juhila, Juuso; Turkki, Riku; Linder, Nina; Lundin, Johan; Kankainen, Matti; Ristimaki, Ari; Koski, Anniina; Liikanen, Ilkka; Oksanen, Minna; Nettelbeck, Dirk M.; Kairemo, Kalevi; Partanen, Kaarina; Joensuu, Timo; Kanerva, Anna; Hemminki, Akseli (2015)
    Oncolytic viruses that selectively replicate in tumor cells can be used for treatment of cancer. Accumulating data suggests that virus induced oncolysis can enhance anti-tumor immunity and break immune tolerance. To capitalize on the immunogenic nature of oncolysis, we generated a quadruple modified oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor (GMCSF). Ad5/3-E2F-Delta 24-GMCSF (CGTG-602) was engineered to contain a tumor specific E2F1 promoter driving an E1 gene deleted at the retinoblastoma protein binding site ("Delta 24"). The fiber features a knob from serotype 3 for enhanced gene delivery to tumor cells. The virus was tested preclinically in vitro and in vivo and then 13 patients with solid tumors refractory to standard therapies were treated. Treatments were well tolerated and frequent tumor-and adenovirus-specific T-cell immune responses were seen. Overall, with regard to tumor marker or radiological responses, signs of antitumor efficacy were seen in 9/12 evaluable patients (75%). The radiological disease control rate with positron emission tomography was 83% while the response rate (including minor responses) was 50%. Tumor biopsies indicated accumulation of immunological cells, especially T-cells, to tumors after treatment. RNA expression analyses of tumors indicated immunological activation and metabolic changes secondary to virus replication.
  • Quixabeira, Dafne C. A.; Cervera-Carrascon, Victor; Santos, Joao M.; Clubb, James H. A.; Kudling, Tatiana V.; Basnet, Saru; Heiniö, Camilla; Grönberg-Vähä-Koskela, Susanna; Anttila, Marjukka; Havunen, Riikka; Kanerva, Anna; Hemminki, Akseli (2022)
    Intratumoral immunotherapies are entering clinical use but concerns remain regarding their effects on non-injected tumors. Here, we studied the impact of local treatment with an adenovirus coding for TNFa and IL-2 on systemic antitumor response in animals receiving aPD-1 (anti-programmed cell death protein 1) therapy. Using bilateral murine melanoma models, we tested systemic tumor response to combined therapy with anti-PD-1 and an adenovirus coding for TNFa and IL-2 ("virus"). Virus was given intratumorally (to one of the two tumors only) and aPD-1 monoclonal antibody systemically. We evaluated both tumors' response to treatment, overall survival, metastasis development, and immunological mechanisms involved with response. Consistent tumor control was observed in both injected and non-injected tumors, including complete response in all treated animals receiving aPD-1+ virus therapy. Mechanistically, virus injections enabled potent effector lymphocyte response locally, with systemic effects in non-injected tumors facilitated by aPD-1 treatment. Moreover, adenovirus therapy demonstrated immunological memory formation. Virus therapy was effective in preventing metastasis development. Local treatment with TNFa and IL-2 coding adenovirus enhanced systemic response to aPD-1 therapy, by re-shaping the microenvironment of both injected and non-injected tumors. Therefore, our pre-clinical data support the rationale for a trial utilizing a combination of aPD-1 plus virus for the treatment of human cancer.
  • Sahi, Helka; Their, Jenny; Gissler, Mika; Koljonen, Virve (2020)
    Merkel cell carcinoma (MCC) is a rare cutaneous carcinoma that has gained enormous interest since the discovery of Merkel cell polyoma virus, which is a causative oncogenic agent in the majority of MCC tumours. Increased research has focused on effective treatment options with immuno-oncology. In this study, we reviewed the real-world data on different treatments given to MCC patients in Finland in 1986-2016. We used the Finnish Cancer Registry database to find MCC patients and the Hospital Discharge Register and the Cause-of-Death Register to obtain treatment data. We identified 376 MCC patients and 33 different treatment entities and/or combinations of treatment. An increase was noted in the incidence of MCC since 2005. Therefore, the cohort was divided into two groups: the "early" group with time of diagnosis between years 1986 and 2004 and the "late" group with time of diagnosis between 2005 and 2016. The multitude of different treatment combinations is a relatively new phenomenon; before the year 2005, only 11 treatments or treatment combinations were used for MCC patients. Our data show that combining radiation therapy with simple excision provided a survival advantage, which was, however, lost after adjustment for stage or age. Our registry study serves as a baseline treatment efficacy comparison as we move into the age of immunotherapy in MCC. Standardizing the treatment of MCC patients in Finland requires more work on awareness and multidisciplinary co-operation.
  • Gao, Yan; Tong, Haibei; Li, Jialiang; Li, Jiachen; Huang, Di; Shi, Jisen; Xia, Bing (2021)
    Nanomedicines have been designed and developed to deliver anticancer drugs or exert anticancer therapy more selectively to tumor sites. Recent investigations have gone beyond delivering drugs to tumor tissues or cells, but to intracellular compartments for amplifying therapy efficacy. Mitochondria are attractive targets for cancer treatment due to their important functions for cells and close relationships to tumor occurrence and metastasis. Accordingly, multifunctional nanoplatforms have been constructed for cancer therapy with the modification of a variety of mitochondriotropic ligands, to trigger the mitochondria-mediated apoptosis of tumor cells. On this basis, various cancer therapeutic modalities based on mitochondria-targeted nanomedicines are developed by strategies of damaging mitochondria DNA (mtDNA), increasing reactive oxygen species (ROS), disturbing respiratory chain and redox balance. Herein, in this review, we highlight mitochondria-targeted cancer therapies enabled by nanoplatforms including chemotherapy, photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), sonodynamic therapy (SDT), radiodynamic therapy (RDT) and combined immunotherapy, and discussed the ongoing challenges.
  • Garg, Abhishek D.; Galluzzi, Lorenzo; Apetoh, Lionel; Baert, Thais; Birge, Raymond B.; Bravo-San Pedro, Jose Manuel; Breckpot, Karine; Brough, David; Chaurio, Ricardo; Cirone, Mara; Coosemans, An; Coulie, Pierre G.; De Ruysscher, Dirk; Dini, Luciana; de Witte, Peter; Dudek-Peric, Aleksandra M.; Faggioni, Alberto; Fucikova, Jitka; Gaipl, Udo S.; Golab, Jakub; Gougeon, Marie-Lise; Hamblin, Michael R.; Hemminki, Akseli; Herrmann, Martin; Hodge, James W.; Kepp, Oliver; Kroemer, Guido; Krysko, Dmitri V.; Land, Walter G.; Madeo, Frank; Manfredi, Angelo A.; Mattarollo, Stephen R.; Maueroder, Christian; Merendino, Nicolo; Multhoff, Gabriele; Pabst, Thomas; Ricci, Jean-Ehrland; Riganti, Chiara; Romano, Erminia; Rufo, Nicole; Smyth, Mark J.; Sonnemann, Juergen; Spisek, Radek; Stagg, John; Vacchelli, Erika; Vandenabeele, Peter; Vandenberk, Lien; Van den Eynde, Benoit J.; Van Gool, Stefaan; Velotti, Francesca; Zitvogel, Laurence; Agostinis, Patrizia (2015)
    The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall mmunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other mmunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.
  • Hamdan, Firas; Ylösmäki, Erkko; Chiaro, Jacopo; Giannoula, Yvonne; Long, Maeve; Fusciello, Manlio; Feola, Sara; Martins, Beatriz; Feodoroff, Michaela; Antignani, Gabriella; Russo, Salvatore; Kari, Otto; Lee, Moon; Järvinen, Petrus; Nisen, Harry; Kreutzman, Anna; Leusen, Jeanette; Mustjoki, Satu; McWilliams, Thomas G.; Grönholm, Mikaela; Cerullo, Vincenzo (2021)
    Background Despite the success of immune checkpoint inhibitors against PD-L1 in the clinic, only a fraction of patients benefit from such therapy. A theoretical strategy to increase efficacy would be to arm such antibodies with Fc-mediated effector mechanisms. However, these effector mechanisms are inhibited or reduced due to toxicity issues since PD-L1 is not confined to the tumor and also expressed on healthy cells. To increase efficacy while minimizing toxicity, we designed an oncolytic adenovirus that secretes a cross-hybrid Fc-fusion peptide against PD-L1 able to elicit effector mechanisms of an IgG1 and also IgA1 consequently activating neutrophils, a population neglected by IgG1, in order to combine multiple effector mechanisms. Methods The cross-hybrid Fc-fusion peptide comprises of an Fc with the constant domains of an IgA1 and IgG1 which is connected to a PD-1 ectodomain via a GGGS linker and was cloned into an oncolytic adenovirus. We demonstrated that the oncolytic adenovirus was able to secrete the cross-hybrid Fc-fusion peptide able to bind to PD-L1 and activate multiple immune components enhancing tumor cytotoxicity in various cancer cell lines, in vivo and ex vivo renal-cell carcinoma patient-derived organoids. Results Using various techniques to measure cytotoxicity, the cross-hybrid Fc-fusion peptide expressed by the oncolytic adenovirus was shown to activate Fc-effector mechanisms of an IgA1 (neutrophil activation) as well as of an IgG1 (natural killer and complement activation). The activation of multiple effector mechanism simultaneously led to significantly increased tumor killing compared with FDA-approved PD-L1 checkpoint inhibitor (Atezolizumab), IgG1-PDL1 and IgA-PDL1 in various in vitro cell lines, in vivo models and ex vivo renal cell carcinoma organoids. Moreover, in vivo data demonstrated that Ad-Cab did not require CD8+ T cells, unlike conventional checkpoint inhibitors, since it was able to activate other effector populations. Conclusion Arming PD-L1 checkpoint inhibitors with Fc-effector mechanisms of both an IgA1 and an IgG1 can increase efficacy while maintaining safety by limiting expression to the tumor using oncolytic adenovirus. The increase in tumor killing is mostly attributed to the activation of multiple effector populations rather than activating a single effector population leading to significantly higher tumor killing.
  • Ylösmäki, Erkko; Fusciello, Manlio; Martins, Beatriz; Feola, Sara; Hamdan, Firas; Chiaro, Jacopo; Ylösmäki, Leena; Vaughan, Matthew J.; Viitala, Tapani; Kulkarni, Prasad S.; Cerullo, Vincenzo (2021)
    Background Intratumoral BCG therapy, one of the earliest immunotherapies, can lead to infiltration of immune cells into a treated tumor. However, an increase in the number of BCG-induced tumor-specific T cells in the tumor microenvironment could lead to enhanced therapeutic effects. Methods Here, we have developed a novel cancer vaccine platform based on BCG that can broaden BCG-induced immune responses to include tumor antigens. By physically attaching tumor-specific peptides onto the mycobacterial outer membrane, we were able to induce strong systemic and intratumoral T cell-specific immune responses toward the attached tumor antigens. These therapeutic peptides can be efficiently attached to the mycobacterial outer membrane using a poly-lysine sequence N-terminally fused to the tumor-specific peptides. Results Using two mouse models of melanoma and a mouse model of colorectal cancer, we observed that the antitumor immune responses of BCG could be improved by coating the BCG with tumor-specific peptides. In addition, by combining this novel cancer vaccine platform with anti-programmed death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy, the number of responders to anti-PD-1 immunotherapy was markedly increased. Conclusions This study shows that intratumoral BCG immunotherapy can be improved by coating the bacteria with modified tumor-specific peptides. In addition, this improved BCG immunotherapy can be combined with ICI therapy to obtain enhanced tumor growth control. These results warrant clinical testing of this novel cancer vaccine platform.
  • Liikanen, Ilkka; Basnet, Saru; Quixabeira, Dafne C. A.; Taipale, Kristian; Hemminki, Otto; Oksanen, Minna; Kankainen, Matti; Juhila, Juuso; Kanerva, Anna; Joensuu, Timo; Tähtinen, Siri; Hemminki, Akseli (2022)
    Background Oncolytic viruses are a potent form of active immunotherapy, capable of invoking antitumor T-cell responses. Meanwhile, less is known about their effects on immune checkpoints, the main targets for passive immunotherapy of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3) is a coinhibitory checkpoint driving T-cell exhaustion in cancer. Here we investigated the effects of oncolytic adenovirus on the TIM-3 checkpoint on tumor-infiltrating immune cells and clinical impact in patients with cancer receiving oncolytic immunotherapy. Methods Modulation of TIM-3 expression on tumor-infiltrating immune cells was studied preclinically in B16 melanoma following intratumoral treatment with Ad5/3 increment 24-granulocyte-macrophage colony-stimulating factor oncolytic adenovirus. We conducted a retrospective longitudinal analysis of 15 patients with advanced-stage cancer with tumor-site biopsies before and after oncolytic immunotherapy, treated in the Advanced Therapy Access Program (ISRCTN10141600, April 5, 2011). Following patient stratification with regard to TIM-3 (increase vs decrease in tumors), overall survival and imaging/marker responses were evaluated by log-rank and Fisher's test, while coinhibitory receptors/ligands, transcriptomic changes and tumor-reactive and tumor-infltrating immune cells in biopsies and blood samples were studied by microarray rank-based statistics and immunoassays. Results Preclinically, TIM-3(+) tumor-infiltrating lymphocytes (TILs) in B16 melanoma showed an exhausted phenotype, whereas oncolytic adenovirus treatment significantly reduced the proportion of TIM-3(+) TIL subset through recruitment of less-exhausted CD8(+) TIL. Decrease of TIM-3 was observed in 60% of patients, which was associated with improved overall survival over TIM-3 increase patients (p=0.004), together with evidence of clinical benefit by imaging and blood analyses. Coinhibitory T-cell receptors and ligands were consistently associated with TIM-3 changes in gene expression data, while core transcriptional exhaustion programs and T-cell dysfunction were enriched in patients with TIM-3 increase, thus identifying patients potentially benefiting from checkpoint blockade. In striking contrast, patients with TIM-3 decrease displayed an acute inflammatory signature, redistribution of tumor-reactive CD8(+) lymphocytes and higher influx of CD8(+) TIL into tumors, which were associated with the longest overall survival, suggesting benefit from active immunotherapy. Conclusions Our results indicate a key role for the TIM-3 immune checkpoint in oncolytic adenoviral immunotherapy. Moreover, our results identify TIM-3 as a potential biomarker for oncolytic adenoviruses and create rationale for combination with passive immunotherapy for a subset of patients.